Mercaptosuccinamic derivatives of aminosteroids



United States Patent M 3,382,257 MERCAPTOSUCCINAMIC DERIVATIVES OFAMINOSTEROIDS Harvey E. Alburn, West Chester, Norman H. Grant,

Wynnewood, and Donald E. Clark, Norristown, Pa., assignors to AmericanHome Products Corporation, New York, N.Y., a corporation of Delaware NoDrawing. Filed July 12, 1965, Ser. No. 471,402

- 4 Claims. (Cl. 260397.1)

This invention relates to compositions of matter classified in the artof chemistry as mercaptosuccinamic derivatives of aminosteroids.

The claimed compositions reside in the concept of chemical compounds inwhich there is attached to the amino group of a 3-aminosteroid a3-mercaptosuccinamido group.

The claimed compounds possess the inherent general physicalcharacteristics of being crystalline solids. These compounds possess thecharacteristic reactivity of mercaptans permitting selective formationof mixed disulfide steroids and sulfonic acid steroids. In addition,their alkali metal salts are quite water soluble. These characteristicstaken together with the nature of the starting materials, their spectraldata and the mode of synthesis positively confirm the structure of theclaimed compounds.

As determined by recognized and accepted pharmacological test proceduresthe claimed compounds exhibit pharmacological activity as antimicrobialand antilipemic agents.

The manner and process of making the invention will now be described soas to enable persons skilled in the art of chemistry to make and use thesame as follows:

The preferred starting materials for the compounds of this invention arefuntumine and funtumidine.

The preparation of the claimed compounds is illustrated as follows:

II I X is -o-o113, CHCH3, Nrroocm, or NH2 3,382,257 Patented May 7, 1968The reaction depicted herein above is carried out by reactingS-acetylmercaptosuccinic anhydride (I) with a selected aminosteroid(II). This reaction preferably is carried out in an inert solvent suchas dioxane and at room temperature. Following removal of the solvent,the residue from the reaction is treated with a nucleophilic agent suchas hydroxylamine or hydrazine to give the final product.

The process of the invention also can be carried out with the followingstarting materials: 3-aminopregnanes such as holamine, holaphyllamine,holaphylline, paravallarine; ZO-aminopregnanes such as funtuphyllamineA, funtuphyllamine B, funtumafrine B, holafebrine; and compounds of theholarrhimine group such as holarrhidine, holarrhimine,(3)-N-methylholarrhimine, and N-methylholarrhimine. Further details onthese compounds appear in J. Pharmacy and Pharmacol. 14,469 (1962).

It will be readily appreciated from the nature of the starting compoundslisted above that these may be substituted anywhere along the nucleus bysimple substituents such as halo (lower) alkyl, lower alkoxy and thelike. Similarly, substituent X may be an acetyl, hydroxyethyl,:acetylamino or an amino group. Obviously, where X is an amino group, asecond acyl group may be introduced into the molecule giving thebis-compound. The presence of the foregoing substituents on the moleculeof the claimed compounds does not interfere with the desirablepharmacological properties of the corresponding unsubstituted compounds.The substituted compounds are full equivalents of such compounds and canbe used for the same purposes.

The claimed compounds can, if desired, be converted into their non-toxicalkali metal salts by conventional techniques. The following examplesillustrate the best mode of producing the invention:

Example 1.N-( 17,8-acetamido-5 ot-androstan-Im-yl 3-mercaptosuccinamicacid The product is active against NWS Influenza virus and against B.subtilis 6633.

Example 2.3a- 3-mercaptosuccinamido)-5apregnan-ZO-one A mixture of 700mg. of funtumine, 384 mg. of S- acetylmercaptosuccinic anhydride, and 1ml. of pyridine in ml. of dioxane was stirred at room temperature. After2 hours, 5.6 milliequivalents of NaOH was added, and the solution wasallowed to stand for 20 minutes. It was then evaporated to dryness, andthe solid was dissolved in water, acidified with 1.5 ml. 4 N HCl, andfiltered. The insoluble portion was thoroughly washed with water, thendissolved in ml. of Water with addition of alkali to pH 9.5, filteredand precipitated again by adding excess HCl. After washing with water,the product was dried under vacuum at room temperature.

Example 3.-N,N'-(5ot-androstan-3a,17,B-diyl)bis (3-mercaptosuccinamicacid) A mixture of 2 grams of 5a-androstane-3a, 17,8-diamine, 2.4 gramsof S-acetylmercaptosuccinic anhydride, '1

ml. of triethylamine, and 100 ml. of dioxane was stirred for 3 hours atroom temperature. Another ml. of triethylamine was added and the mixtureallowed to stand 17 hours. There was then added 15 ml. of previouslyneutralized 1 M NH OH, and the mixture was stirred for 15 minutes andthen evaporated nearly to dryness. 100 ml. of water was added, and themixture was filtered. The filtrate was adjusted to pH 1.2 with 6 N HCland the precipitate collected. It was suspended in water, brought to pH9, refluxed with carbon, and filtered. The filtrate was acidified to pH1.2, and the precipitate was collected and dried. The product wasextracted into hot ethanol, and the solvent was removed under vacuum.The solid was washed with water and dried over phosphorous pentoxide,giving 2.3 grams. The compound is active in lowering blood lipids and isactive against NWS Influenza virus.

Example 4.3a-(3-mereaptosuccinamido)-5apregnan-ZOa-ol A mixture of 3.4grams of funtumidine and 1.85 grams of S-acetylmercaptosuccinicanhydride was allowed to stand at room temperature. After 24 hours and42 hours, 11 ml. aliquots of 1 N NaOH were added. The test forhydroxamic acid formation was now negative, and the suspension wasevaporated to dryness. The solid was extracted with hot ethanol and theextract passed through a Dowex-l (OH) column. The efiiuent and wash werepooled and filtered. The filtrate was evaporated to dryness, the solidwas washed with water and then extracted into 25 ml. of dioxane. Theextract was then evaporated to dryness, giving 1.85 grams of product.

The claimed compounds either in the form of their free acids or in theform of their alkali metal salts may be combined with conventionalpharmacological diluents and carriers to form usual dosage forms.

What is claimed is:

1. N (175-acetamido-Sa-andrOStan-Ba-yl)-3-mercaptosuccinamic acid.

2. 3 oc- 3-mercaptosuccinamido -5a-pregnan-20-one.

3. N,N' (5a androstan-3a,17fl-diyl)bis(3-mercaptosuccinamic acid).

4. 3 cc- (3-rnercaptosuccinamido) -5a-pregnan-20a-ol.

References Cited UNITED STATES PATENTS 2/1965 Stevens 167-65 2/1965Davis 167-65

1. N-(17B-ACETAMIDO-KA-ANDROSTAN-3A-YL)-3-MERCAPTOSUCCINAMIC ACID.